DESCRIPTION(Verbatim from Applicant's Abstract): The long-range goal of this project is to elucidate the molecular mechanisms that control Schwann cell differentiation. The aim of the current application is to investigate the mechanisms by which heregulin growth factors activate signaling receptors on Schwann cells. Heregulins are key regulators of Schwann cell proliferation, differentiation, and survival. Nerve cells are a major source of heregulins in peripheral nerves, and heregulins associated with axonal membranes have been shown to promote Schwann cell proliferation and survival. At least 12 heregulin isoforms are known to be produced by alternative splicing. These isoforms exhibit considerable structural variability. Heregulins activate intracellular signaling pathways in Schwann cells by binding to the transmembrane receptor kinases erbB2 and erbB3. Receptor binding is mediated by a conserved domain of approximately 50 amino acids that is present in all heregulins. The proposed experiments will examine the hypothesis that structural differences among heregulin isoforrns alter their ability to interact with target cells, such as Schwann cells. This results, in part, from differences in membrane association and interaction of certain heregulin isoforms with cell surface heparan sulfate molecules. The specific aims address the following questions related to heregulin function and Schwann cells. What are the effects of differences in heregulin structure on receptor binding, internalization and activation of Schwann cells? How does interaction with heparan sulfate proteoglycans affect the activity of heregulins? These studies will be carried out with rat Schwann cells grown in tissue culture and recombinant heregulins. Mutagenesis of heregulin isoforms will be used to identify particular structural domains that produce functional differences. The information derived from these studies will facilitate the understanding and treatment of human diseases of the peripheral nervous system and regeneration